Prostate cancer (PCa) is the most prevalent cancer among men in the United States (US), affecting one man in six. Recent studies have shown that the glucose-lowering medication metformin and the lipid-lowering medication statins could reduce PCa risk. For those without medication contraindications, metformin is recommended by the American Diabetes Association as the first-line glucose-lowering agent for individuals with type 2 diabetes (T2DM); while statins are recommended by the American College of Physicians for all individuals with T2DM because of the high prevalence of dyslipidemia comorbidity in this population. As 11.2% (~13 millions) of the US men have T2DM, a continuously rising epidemic in the US, it is important to study the effects of metformin and statins on PCa in this population due to their prevalent use of these medications. Particularly, among men with PCa, diabetes is associated with an increased risk of high-grade PCa. Thus studying the joint effects of metformin and statins on PCa in men with T2DM may have substantial public health impact. Knowledge Gaps. (G1) The glucose-lowering effect of metformin could be a potential surrogate for assessing (i) the likelihood of the AMPK pathway being activated by metformin, and hence (ii) the variation of metformin effect on PCa risk reduction. The lipid-lowering effect of statins could be a potential surrogate for assessing (i) the likelihood of the mevalonate pathway being blocked by statins, and hence (ii) the variation of statins effect on PCa risk reduction. Currently no clinical studies exist to assess whether effects of metformin and statins on PCa vary by the corresponding glucose-lowering and the lipid-lowering effects. (G2) Both hyperglycemia and dyslipidemia are associated with an increased PCa risk, and the two are correlated. There may exist a synergistic effect associated with metformin and statin on PCa, potentially mediated through their glucose- and lipid- lowering effects. Currently, no clinical studies exist to assess this joint effect. Specific Aims. To conduct a proof-of-principle study to address Knowledge Gaps (G1) and (G2) by developing a causally interpretable prediction model to assess the joint impacts of metformin and statins on PCa incidence in a nine-year historical cohort of men with T2DM from the nationwide Veteran Administrative Health Care System. (Aim 1) Assess the variation of glucose-lowering effect of metformin and the lipid- lowering effect of statins over time. (Aim 2) Assess the independent effects of metformin and statins on PCa incidence mediated/moderated by the glucose-lowering and lipid-lowering effects. (Aim 3) Assess the joint effects of metformin and statins on PCa incidence. (Aim 4) Assess the differential effects of metformin and statins on the high-grade PCa vs. low-grade of PCa. PUBLIC HEALTH RELEVANCE: Metformin and Statins are commonly used medications in men with type 2 diabetes, a population at increased risk for high-grade prostate cancer. If it can be demonstrated that both medications independently or jointly reduce prostate cancer incidence significantly in men with type 2 diabetes, then this proposed research has the potential to lead to interventions with great public health benefit because of the common occurrence of prostate cancer and increasing prevalence of type 2 diabetes.